Two impediments which limit the effectiveness of conventional cancer treatment are the lack of a significant differential response between normal and tumor tissue and the development of biochemical resistance to commonly used therapies. Recent evidence suggests that the latter limitation is determined, in part, by the genetic makeup of the tumor cell. This research proposal will examine the general hypothesis that the therapeutic index of cancer radiotherapy can be enhanced by employed suicide gene therapy as an adjuvant therapy and by manipulating the p53 status of the tumor cell. Recombinant retroviruses encoding a novel E. Coli cytosine deaminase (CD)/Herpes Simplex Virus thymidine kinase (HSV-1TK) fusion gene have been generated and used to express the CD/HSV-1 TK fusion protein in tumor cells. We will test hypothesis that these two suicide gene systems, when combined, function synergistically to kill tumor cells in vivo. Based on our previous observations that each suicide gene system independently can radiosensitize tumor cells in vitro, we will test the hypothesis that expression of the CD/HSV-1 TK fusion protein will result in tumor radiosensitization in vivo. Because recent studies have indicated that the efficacy of chemotherapy and radiotherapy is dependent on tumor p53 status, we will test the hypothesis that co-expression of wild-type p53 will increase the effectiveness of the combined suicide gene therapy/radiotherapy approach. Recombinant adenoviruses will be used to deliver the CD/HSV-1 TK fusion and p53 genes to tumor cells I vivo. We will test the hypothesis that this multifaceted approach will be more efficacious at tumor control than either suicide gene therapy or radiotherapy alone. As improvements in locoregional control of tumor could translate into better survival outcomes, this research may provide the rationale upon which future clinical trials using this multifaceted approach will be based.